Integrative Multi-Omics Analysis of Circulating Biomarkers Reveals Targetable Pathways in Pelvic Organ Prolapse
Yajing Huang1, Xiaoyun Yang1, Kewei Chen1
1Department of Obstetrics and Gynecology, Tongji Hospital Affiliated to Tongji University, Putuo District, Shanghai, China.
Introduction:
This study aims to investigate plasma proteins and metabolites causally linked to Pelvic Organ Prolapse (POP), and explore the molecular mechanisms using a proteo-metabolomic Mendelian Randomization (MR) framework.
Methods:
MR was performed to assess causal relationships between genetically predicted plasma proteins and POP risk, utilizing large-scale proteomic GWAS data. Colocalization analysis and replication in independent cohorts were performed to evaluate the robustness of the genetic associations. To explore potential downstream mechanisms, a two-step MR approach was applied to investigate metabolites associated with sTie2. Circulating sTie2 concentrations were measured in clinical plasma samples by ELISA, and plasma metabolic profiles were characterized using untargeted metabolomics in POP patients and matched controls.
Results:
Of the 2,994 circulating proteins examined, 11 showed evidence of a potential causal relationship with POP after multiple testing correction. Among these, soluble Tie2 (sTie2) emerged as a prominent candidate, with similar effect estimates observed across independent datasets. Elevated circulating sTie2 levels in POP patients were further supported by ELISA measurements. Further two-step MR analysis identified 27 metabolites linked to sTie2, with paraxanthine showing a significant positive association with POP susceptibility. Importantly, untargeted metabolomics revealed paraxanthine-related caffeine metabolism as the most significantly enriched KEGG pathway in POP plasma, providing cross-platform validation of the MR-inferred metabolic axis.
Discussion:
These findings indicate that POP may be driven by a previously unrecognized sTie2-paraxanthine axis. This mechanistic link suggests that vascular signaling and metabolic regulation jointly contribute to pelvic floor degeneration, providing a broader framework for understanding disease progression.
Conclusion:
The study identifies sTie2 as a potential causal factor for POP and suggests a new metabolic pathway involving paraxanthine, providing insights into POP pathogenesis and new targets for therapeutic intervention.
